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We here used a mouse model for tuberous sclerosis (TS) carrying a heterozygous deletion of the <jats:italic>Tsc2<\/jats:italic> gene. Loss of <jats:italic>Tsc2<\/jats:italic> function leads to mTOR hyperactivity in mice and patients. In a longitudinal behavioral analysis, we found premature decline of hippocampus\u2010based cognitive functions together with a significant reduction of immediate early gene (IEG) expression. While we did not detect any morphological changes of hippocampal projections and synaptic contacts, molecular markers of neurodegeneration were increased and the mTOR signaling cascade was downregulated in hippocampal synaptosomes. Injection of IGF2, a molecule that induces mTOR signaling, could fully rescue cognitive impairment and IEG expression in aging <jats:italic>Tsc2<\/jats:italic><jats:sup><jats:italic>+\/\u2212<\/jats:italic><\/jats:sup> animals. This data suggests that TS is an exhausting disease that causes erosion of the mTOR pathway over time and IGF2 is a promising avenue for treating age\u2010related degeneration in mTORopathies.<\/jats:p>","DOI":"10.1111\/acel.14318","type":"journal-article","created":{"date-parts":[[2024,8,28]],"date-time":"2024-08-28T05:40:21Z","timestamp":1724823621000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Premature cognitive decline in a mouse model of tuberous sclerosis"],"prefix":"10.1111","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-7700-7320","authenticated-orcid":false,"given":"J.","family":"Krummeich","sequence":"first","affiliation":[{"name":"Institute of Human Genetics University Medical Center of the Johannes Gutenberg University Mainz  Mainz Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"L.","family":"Nardi","sequence":"additional","affiliation":[{"name":"Institute of Anatomy University Medical Center of the Johannes Gutenberg University Mainz  Mainz Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C.","family":"Caliendo","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics University Medical Center of the Johannes Gutenberg University Mainz  Mainz Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"D.","family":"Aschauer","sequence":"additional","affiliation":[{"name":"Institute of Physiology University Medical Center of the Johannes Gutenberg University Mainz  Mainz Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"V.","family":"Engelhardt","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics University Medical Center of the Johannes Gutenberg University Mainz  Mainz Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A.","family":"Arlt","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics University Medical Center of the Johannes Gutenberg University Mainz  Mainz Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J.","family":"Maier","sequence":"additional","affiliation":[{"name":"Institute of Anatomy University Medical Center of the Johannes Gutenberg University Mainz  Mainz Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"F.","family":"Bicker","sequence":"additional","affiliation":[{"name":"Institute of Anatomy University Medical Center of the Johannes Gutenberg University Mainz  Mainz Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M. 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